The invention relates to compounds of the formula I 
in which
R1, R2 independently of one another are each H, A, OA or Hal,
R1 and R2 together are also alkylene having 3-5 carbon atoms, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94,
X is R5, R6 or R4 which is monosubstituted by R7,
R4 is linear or branched alkylene having 1-10 carbon atoms, in which one or two CH2 groups may be replaced by xe2x80x94CHxe2x95x90CHxe2x80x94 groups,
R5 is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms,
R6 is phenyl or phenylmethyl,
R7 is COOH, COCA, CONH2, CONHA, CON(A)2 or CN,
A is alkyl having 1 to 6 carbon atoms and
Hal is F, Cl, Br or I,
and their physiologically acceptable salts.
Pyrimidine derivatives are known, for example, from EP 201 188 or WO 93/06104.
The invention was based on the object of discovering new compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable
The compounds of the formula I can be employed as medicament active compounds in human and veterinary medicine. They can furthermore be employed as intermediates for the preparation of further medicament active compounds.
The invention accordingly provides the compounds of the formula I and a process for the preparation of compounds of the formula I according to claim 1, and of their salts, characterized in that
a) a compound of the formula II 
xe2x80x83in which
X is as defined above
and L is Cl, Br, OH, SCH3 or a reactive esterified OH group
is reacted with a compound of the formula III 
xe2x80x83in which
R1 and R2 are as defined above,
or
b) a radical X in a compound of the formula I is converted into another radical X, for example by hydrolysing an ester group to a COOH group or converting a COOH group into an amide or a cyano group and/or in that a compound of the formula I is converted into one of its salts.
Above and below, the radicals R1, R2, R3, R4, R5, R6, R7, X and L have the meanings given for the formulae I, II and III, unless expressly stated otherwise.
A is alkyl having 1-6 carbon atoms. In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5, or 6 carbon atoms, and is preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.
X is an R4-, R5- or R6-radical which is monosubstituted by R7.
R4 is a linear or branched alkylene radical having 1-10 carbon atoms, where the alkylene radical is preferably, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secbutylene, pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1,1,2- or 1,2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or decylene.
R5 is furthermore, for example, but-2-enylene or hex-3-enylene.
Very particular preference is given to ethylene, propylene or butylene.
R5 is cycloalkylalkylene having 5-12 carbon atoms, preferably, for example, cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene. R5 is also cycloalkyl preferably having 5-7 carbon atoms. Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.
Hal is preferably F, Cl or Br, but also I.
The radicals R1 and R2 may be identical or different and are preferably in the 3- or 4-position of the phenyl ring. Independently of one another they are in each case, for example, H, alkyl, F, Cl, Br or I, or together they are alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. Preferably, they are also in each case alkoxy, such as, for example, methoxy, ethoxy or propoxy.
The radical R7 is preferably, for example, COOH, COOCH3, COOC2H5, CONH2, CON(CH3)2, CONHCH3 or CN.
For the entire invention, all the radicals which occur several times can be identical or different, that is to say independent of one another.
The invention accordingly particularly provides those compounds of the formula I in which at least one of the radicals mentioned has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following part formulae Ia to Id, which correspond to the formula I and wherein the radicals not defined in more detail have the meaning given for the formula I, but in which
in Ia X is phenyl, phenylmethyl or R4 which is substituted by COOH, COOA, CONH2, CONA2, CONHA or CN;
in Ib R1 and R2 together are alkylene having 3-5 carbon atoms, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94O,
X is phenyl, phenylmethyl or R4 which is substituted by COOH, COOA, CONH2, CONA2, CONHA or CN;
in Ic
R1, R2 independently of one another are in each case H, A, OA or Hal,
R1 and R2 together are alkylene having 3-5 carbon atoms, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94O,
X is phenyl, phenylmethyl or R4 which is substituted by COOH, COOA, CONH2, CONA2, CONHA or CN;
in Id R1, R2 independently of one another are in each case H, A, OA or Hal,
R1 and R2 together are also alkylene having 3-5 carbon atoms, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94,
X is cyclohexyl, phenyl, phenylmethyl or alkylene having 2-5 carbon atoms which is monosubstituted by R7,
R7 is COOH or COOA,
A is alkyl having 1 to 6 carbon atoms,
Hal is F, Cl, Br or I.
The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry], Georg-Thieme-Verlag, Stuttgart), and in particular under reaction conditions which are known and suitable for the reactions mentioned. For these reactions, it is also possible to utilize variants which are known per. se and are not mentioned here in more detail.
In the compounds of the formulae II and III, R1, R2, R3, R4, X and n have the meanings given, in particular the preferred meanings given.
If L is a reactive esterified OH group, this is preferably alkylsulphonyloxy having 1-6 carbon atoms (preferably methylsulphonyloxy) or arylsulphonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulphonyloxy, or furthermore also 2-naphthalenesulphonyloxy).
The compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I.
On the other hand, it is possible to carry out the reaction in stages.
The starting materials of the formulae II and III are generally known. If they are not known, they can be prepared by methods known per se. Compounds of the formula II can be obtained, for example, by reacting POCl3 with the corresponding hydroxypyrimidines which are synthesized from thiophene derivatives and CN-substituted alkylenecarboxylic esters (Eur. J. Med. Chem. 23, 453 (1988)). The hydroxypyrimldlnes are prepared either by dehydrogenation of the corresponding tetrahydrobenzothienopyrimidine compounds, or after the cyclization of 2-aminobenzothiophene-3-carboxylic acid derivatives with aldehydes or nitriles which is customary for preparing pyrimidine derivatives (for example Houben-Weyl E9b/2).
Specifically, the reaction of the compounds of the formula II with the compounds of the formula III is carried out in the presence or absence of an inert solvent at temperatures between about xe2x88x9220 and about 150xc2x0, preferably between 20 and 100xc2x0.
The addition of an acid-binding agent, for example an alkyl metal hydroxide, carbonate or bicarbonate or alkaline earth metal hydroxide, carbonate or bicarbonate, or of another alkali metal or alkaline earth metal, preferably potassium, sodium or calcium, salt of a weak acid, or the addition of an organic base, such as triethylamine, dimethylamine, pyridine or quinoline, or of an excess of the amine component may be favourable.
Suitable inert solvents are, For example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methylglycol or ethylglycol), ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide (DMF); nitrites, such as acetonitrile; sulphoxides, such as dimethyl sulphoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the solvents mentioned.
It is furthermore possible to convert a radical X in a compound of the formula I into another radical X, for example by hydrolysing an ester or a cyano group to give a COOH group. Ester groups can be hydrolysed, for example, using NaOH or KOH in water, water/THF or water/dioxane, at temperatures between 0 and 100xc2x0. Carboxylic acids can be converted with, for example, thionyl chloride into the corresponding carbonyl chlorides, and these can be converted into carboxamides. By dehydration in a known manner, these give carbonitriles. 
An acid of the formula I can be converted into the associated acid addition salt using a base, for example by reaction of equivalent amounts of the acid and the base in an inert solvent, such as ethanol, and subsequent evaporation. Possible bases for this reaction are, in particular, those which give physiologically acceptable salts. The acid of the formula I can thus be converted with a base (for example sodium hydroxide or carbonate or potassium hydroxide or carbonate) into the corresponding metal salt, in particular alkalis metal salt or alkalne earth metal salt, or into the corresponding ammonium salt. Possible bases for this reaction are, in particular, also those organic bases which give physiologically acceptable salts, such as, for example, ethanolamine.
On the other hand, a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, and subsequent evaporation. Acids which are suitable for this reaction are, in particular, those which give physiologically acceptable salts. It is thus possible to use inorganic acids, for example sulphuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulphaminic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulphonic or sulphuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinnic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulphonic acid, ethanedisulphonic acid, 2-hydroxyethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, naphthalene-mono- and disulphonic acids and laurylsulphuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for isolation and/or purification of the compounds of the formula I.
The invention furthermore provides the use of the compounds of the formula I and/or their physiologically acceptable salts for the preparation of pharmaceutical formulations, in particular by a non-chemical route. For this use, they can brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid carrier or auxiliary, and if appropriate in combination with one or more further active compounds.
The invention also provides medicaments of the formula I and their physiologically acceptable salts as phosphodiesterase V-inhibitors.
The invention furthermore provides pharmaceutical formulations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.
These Formulations can be used as medicaments in human or veterinary medicine. Possible carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used, in particular, for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the resulting lyophilizates can be used, for example, for the preparation of injection preparations. The formulations a mentioned can be sterilized and/or comprise auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or several other active compounds, for example one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be employed for combating diseases with which an increase in the cGMP(cyclic guanosine monophosohate) level leads to an inhibition or prevention of inflammation and to muscular relaxation. The compounds according to the invention can be used in particular in the treatment of diseases of the cardiovascular system and for the treatment and/or therapy of impaired potency.
For these uses, the substances are generally preferably administered in dosages of between 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg/kg of body weight. However, the specific dose for each patient depends on the most diverse factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the administration time and route, on the rate of elimination, medicament combination and severity of the particular disease to which the therapy applies. Oral administration is preferred.
All the temperatures above and below are stated in 0xc2x0 C. In the following examples, xe2x80x9ccustomary work-upxe2x80x9d means: water is added, if required, the pH is adjusted to between 2 and 10, if required, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulphate and evaporated and the residue is purified by chromatography over silica gel and/or by crystallization.
Mass spectrometry (MS): EI (electron impact ionization) M+; FAB (fast atom bombardment) (M+H)+.